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L0301P50 - Synaptic Transmission
Synaptic Transmission *process of information transfer at a synapse The Synapse *mechanism allowing speedy and efficient signalling between neurons Types *electrical synapses **allow direct transfer of ionic current from one cell to another **occur at specialised sites - gap junctions **very rare *chemical synapses **make up most synapses in the human nervous system **rely on secretion of neurotransmitters **electrical —> chemical —> electrical **occurs in one direction only Presynaptic Neuron Terminal *bulge containing vesicles and release mechanisms = bouton *neurotransmitter ready for release (synthetic enzymes etc) Synaptic Cleft *20nm wide *transmitter diffusion takes 0.1ms *transmitter removal using enzymes and transporters Postsynaptic Neuron *receptive molecules (specific receptors) for the transmitters Composition *neurons are not myelinated at synapses *pre- and post-synaptic membrane is mainly composed of proteins CNS Synapses a) axodendritic b) axiomatic c) axoaxonic *there also are dendodendritic synapses (rare) PNS Synapses *known as neuromuscular junctions *between axons of motion neurons of the spinal cord and skeletal muscle Ion Channels of Neurotransmission Voltage Gated Calcium Channels (CaV) *found at: **pre-synaptic membrane for NT release **post-synaptic membrane for signalling *similar structure to NaV *10 different types: all inactivate, but some types have stronger inactivation than others   Receptor-Gated Channels *ionotropic receptor/channels **AMPA receptors conduct Na+ and K+ **NMDA receptors conduct Na+, K+ , Ca2+ **GABA receptors conduct Cl- Neurotransmitters *responsible for chemical communication between synapses *vesicles of NT in bouton of neurons Types Synthesis and Storage *always synthesised in advance in the cytosol of the axon terminal *transporters (special proteins) then concentrate them into vesicles in the presynaptic terminal where they are stored *approximately similar numbers of NT molecules per vesicle within a bouton **generally from few100s-6000 **variations in number in different neurons and for different neurotransmitters Release *occurs at the bouton where there is a great profusion of CaV channels *docking proteins (SNARE proteins) **have CaV channels on either side **hold vesicle of NT in position for release **influx of Ca2+ results in a conformational change of the protein ***allows lipid bilayers of the vesicle and presynaptic membranes to fuse and thus release the neurotransmitters Process of Release: *when terminal membrane is depolarised (i.e. when AP arrives), CaV channels in the active zones open *Ca2+ enter the cytoplasm of the axon terminal altering the docking proteins *exocytosis - vesicle fuses and releases contents into synaptic cleft *endocytosis: allow recovery of membrane Related Drugs Botox *used in cosmetics and as a therapeutic drug *strategically placed injections can help those with muscle stiffness (cerebral palsy) regain movement *potentially also help those with chronic pain if injected into the spinal cord Conotoxin *found in venom of marine cone snail *appears to blocks CaV channels *nerves to breathing muscles would be affected and would result in hospitalisation if it is widely spread in the body Diffusion *neurotransmitters diffuse across the synaptic cleft to the postsynaptic membrane *estimated to take only 0.1ms Reception - Synaptic Receptors *four or five subunits, with each subunit having 4 transmembrane ™ segments *also has a large extracellular domain to which neurotransmitters bind *are not highly selective *are receptor-gated channels **i.e. form a “hole” when transmitter binds ***TM2 lie close together at rest and move apart to form the pore **thus, receptor becomes a channel which allows ions to pass through into the cell ***called ionotropic receptor/channels *found in high concentrations in the postsynaptic membrane *used by transmitters: **excitatory - e.g. glutamate, acetylcholine **inhibitory - e.g. GABA, glycine Consequence - Synaptic Potentials *activation of receptor turns it into a channel which in turn creates EPSP or IPSP *allows for very fast transmission *inactivate after 5-10ms (much slower than voltage-gated ion channels) Excitatory Pathway - EPSP *Na+ enters the cell, while K+ leaves cell, due to lack of selectivity **~4Na+:1K+ @ -60mV *net positive ion influx *cell membrane rendered less negative (depolarisation) *create excitatory post-synaptic potential (EPSP) as the response **it is graded i.e. greater number of channels opened, the larger the EPSP **∴ amplitude depends upon the number and properties of the junctional receptors *if sufficiently large enough to reach threshold, EPSP may result in the opening of NaV channels to generate the next AP Inhibitory Pathway - IPSP *can either lead to: **influx of Cl- ***binding opens up Cl- channels instead = increase in pCl- ***leads to hyperpolarization (further from threshold) if Vm reaches <-74mV ***has no effect if Vm = -74mV ****Cl- negativity will “cancel out” incoming positivity (from Na+) = EPSP amplitude reduced *increase in K+ conductance **hyperpolarisation as Ek = -94mV Quantal Release of Transmitter *Within each system: **each release site dispenses, at most, only one docked vesicle per action potential **vesicles contain a quantum (defined number) of transmitter **quantal release results in EPSPs of approximately equal amplitude Common Neurotransmitters Glutamate *most common excitatory NT in the CNS *amino acid - very small simple molecule *act on receptors - NMDA and non-NMDA AMPA Receptor *a non-NMDA-type ionotropic receptor *only binding with it will result in activity (movement of Na+ and K+) NMDA Receptor *no instant activity due to magnesium ion blocking the pore **repels the Na+ and K+ ions *Mg2+ ion will be removed when depolarisation occurs **i.e. after binding with the AMPA receptor has occurred *allows influx of Na+ and Ca2+; efflux of K+ *Ca2+ and its movement: **is a secondary messenger which initiates many other pathways **essential for neuroplasticity - forming memory **however too much will also have detrimental effects Acetylcholine *most common excitatory NT in PNS *binds to ionotropic nicotinic receptors **found at neuromuscular junctions **also found in the brain ***contributes to dementia **allows influx of Ca2+ *can also bind to muscuranic metabotropic receptors found in the heart GABA *inhibitory amino acid NT *trigger opening of Cl- channels which cause hyper polarisation *causes subthreshold events: **no AP regenerated **membrane is leaky ***variably - least in myelinated regions **continuous loss of amplitude ***for event arising at tip of long dendrite, may be very small by the time it reaches the soma